Despite its tendency to metastasize and grow multifocally, papillary thyroid carcinoma (PTC), the most common endocrine malignancy, usually displays an indolent clinical course. Although this behavior probably reflects the inherent low growth potential of PTC cells, it has been postulated that the striking inflammatory reaction often present in PTC represents the activation of a protective, tumor-induced immune response. In a recent immunohistochemical study, we reported that immunoglobulin (IgG) and complement (C3d, C4d and C5) are specifically deposited in PTC tumor tissue. Endeavors were then made to isolate and identify tumor-associated antigens. Immunoprecipitation employing the serum and tumor tissue of PTC patients produced two bands by SDS-PAGE, at approximately 34.5 and 35 kD, which were not present in normal thyroid tissue. Three tryptic peptides of the 35 kD band were sequenced, identifying it as a fragment of cytokeratin 1, a structural protein not normally expressed in the thyroid. The results indicate a tumor-specific antibody response against an aberrantly expressed protein in PTC.